Annexin A6 mediates calcium-dependent exosome secretion during plasma membrane repair
Exosomes are an extracellular vesicle (EV) subtype that is secreted upon fusion of multivesicular bodies (MVBs) with the plasma membrane. Exosomes may participate in intercellular communication and have utility as disease biomarkers; however, little is known regarding the physiological stimuli that induce their secretion. Ca2+ influx promotes exosome secretion, raising the possibility that exosomes are secreted during the Ca2+-dependent plasma membrane repair of tissues damaged by mechanical stress in vivo. To determine whether exosomes are secreted upon plasma membrane damage, we developed sensitive assays to measure exosome secretion in intact and permeabilized cells. Our results suggest that exosome secretion is coupled to Ca2+-dependent plasma membrane repair. We find that annexin A6 (ANXA6), a well-known plasma membrane repair protein, is recruited to MVBs in the presence of Ca2+ and required for Ca2+-dependent exosome secretion, both in intact and in permeabilized cells. ANXA6 depletion stalls MVBs at the cell periphery, and ANXA6 truncations localize to different membranes, suggesting that ANXA6 may serve to tether MVBs to the plasma membrane. We find that cells secrete exosomes and other EVs upon plasma membrane damage and propose that repair-induced secretion may contribute to the pool of EVs present within biological fluids.
All data generated or analyzed during this study are included in the manuscript and supporting source data files. Source Data files have been provided for Figure 2, Figure 2 - Figure supplement 1, Figure 3, Figure 4, and Figure 4 - Figure supplement 1. Video Files have been provided for Figure 6 - Videos 1- 6.
Article and author information
Howard Hughes Medical Institute
- Randy Schekman
Sergey Brin Family Foundation (N/A)
- Randy Schekman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Suzanne R Pfeffer, Stanford University, United States
- Received: January 31, 2023
- Accepted: May 18, 2023
- Accepted Manuscript published: May 19, 2023 (version 1)
© 2023, Williams et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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